1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds

ABSTRACT

1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds represented by the formula: ##STR1## wherein X represents a hydrogen atom or a halogen atom; Y represents a covalent bond, a straight- or branched-chain alkylene group having 1 to 6 carbon atoms, or a straight- or branched-chain alkenylene group having 2 to 6 carbon atoms; R represents a hydrogen atom, or a straight- or branched-chain alkyl group having 1 to 6 carbon atoms; and pharmaceutically acceptable salts thereof. The compounds represented above are novel potent and long-lasting histamine HI-receptor antagonist with less-topical irritation, and can be topically administered by inhalation for the treatment of bronchial asthma.

This is a National Stage Application under 35USC371 of InternationalApplication PCT/JP94/00787 filed May 16, 1994.

This is a National Stage Application under 35USC371 of InternationalApplication PCT/JP94/00787 filed May 16, 1994.

TECHNICAL FIELD

The present invention relates to novel1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds and pharmaceuticallyacceptable salts thereof being useful as therapeutic agents.

More particularly, the present invention relates to novel1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds represented by theformula: ##STR2## wherein X represents a hydrogen atom or a halogenatom; Y represents a covalent bond, a straight- or branched-chainalkylene group having 1 to 6 carbon atoms, or a straight- orbranched-chain alkenylene group having 2 to 6 carbon atoms; R representsa hydrogen atom, or a straight- or branched-chain alkyl group having 1to 6 carbon atoms; and pharmaceutically acceptable salts thereof.

BACKGROUND ART

Histamine H₁ -receptor antagonists are widely employed in orally for thetreatment of bronchial asthma, and it is reported that they often showsystemic adverse actions such as sedation or arrhythmogenetic activity.Therefore, topical treatment using the antagonists has been attempted inorder to avoid such adverse actions. However, the methods areunsuccessful because the antagonists have strong bronchia irritationwhen inhaled directly to the bronchia.

Thus, there remains a need for the development of histamine H₁ -receptorantagonists which can be directly inhaled to the bronchia for thetreatment of bronchial asthma with less irritation to bronchial tissues.

European Patent Application Unexamined Publication No. 5,318 discloses abenzimidazole compound represented by the formula: ##STR3## wherein Zrepresents a hydrogen atom or a fluorine atom; A represents a methoxygroup, an ethoxy group, a 2-propenyloxy group, a hydroxy group, amethoxycarbonylmethyloxy group, an methoxycarbonylmethyloxy group, acyanomethyloxy group, a methylthio group, a methanesulfonyl group, anamino group, a nitro group, a fluorine atom or a chlorine atom. Inaddition, of the above benzimidazole compounds, the compound representedby the formula: ##STR4## has been employed (general name: Astemizole) asoral histamine H₁ -receptor antagonist. However, any topical formulationof this drug applied to the bronchia has not been acceptable in practicedue to strong irritation to bronchial tissues.

The 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of the presentinvention are novel compounds, and have not been disclosed or suggestedin any prior literature.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide novel1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds and pharmaceuticallyacceptable salts thereof which are useful as therapeutic agents for thetreatment of bronchial asthma by inhalation to the bronchia.

Another object of the present invention is to provide pharmaceuticalcomposition containing a 1-(2-benzimidazolyl)-1,5-diazacyclooctanecompound or a pharmaceutically acceptable salt thereof as an activeingredient, which is effective for the treatment of bronchial asthma byinhalation to the bronchia.

A further object of the present invention is to provide the use of a1-(2-benzimidazolyl)-1,5-diazacyclooctance compound or apharmaceutically acceptable salt thereof for the manufacture of apharmaceutical for the treatment of bronchial asthma.

Still further object of the present invention is to provide a method forthe treatment of bronchial asthma, which comprises inhaling to thebronchia a therapeutically effective amount of a1-(2-benzimidazolyl)-1,5-diazacyclooctane compound or a pharmaceuticallyacceptable salt thereof.

Other objects, feature and advantages of the present invention willbecome apparent from the following description of the invention.

The present invention provides novel1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds and pharmaceuticallyacceptable salts thereof which exhibit potent antihistaminic andantiallergic activities with less topical irritations, and particularlyirritation to bronchial tissues. Thus, the1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of the presentinvention can be useful as therapeutic agents for the treatment ofbronchial asthma by inhalation to the bronchia.

In the definition of the compounds represented by the formula (I), theterm "alkylene group" as used herein means a straight- or branched-chainalkylene group having 1 to 6 carbon atoms such as a methylene group, anethylene group, a trimethylene group, a tetramethylene group, apentamethylene group, a hexamethylene group, a 1,1-dimethylethylenegroup, a propylene group, an ethylethylene group, a 1-methyltrimethylenegroup, a 1,1-dimethyltrimethylene group, a 2-methyltrimethylene group, a2,2-dimethyltrimethylene group, and the like.

The term "alkenylene group" as used herein means a straight- orbranched-chain alkenylene group having 2 to 6 carbon atoms such as avinylene group, a propenylene group, an isopropenylene group, a1-butenylene group, a 2-butenylene group, and the like.

The term "alkyl group" as used herein means a straight- orbranched-chain alkyl group having 1 to 6 carbon atoms such as a methylgroup, an ethyl group, a n-propyl group, an isopropyl group, a n-butylgroup, a tert-butyl group, a sec-butyl group, a n-pentyl group, an-hexyl group, and the like.

The term "a halogen atom" as used herein means a fluorine atom, achlorine atom, a bromine atom, or an iodine atom.

A 1-(2-benzimidazolyl)-1,5-diazacyclooctane compound of the formula (I)of the present invention is a novel compound and can be prepared asfollows. For example, it can be prepared by a reaction of a1-(2-benzimidazolyl)-1,5-diazacyclooctane compound represented by thefollowing formula or an acid addition salt thereof: ##STR5## wherein Xhas the same meaning as defined above, with a phenylethyl bromidecompound represented by the formula: ##STR6## wherein R¹ represents astraight- or branched-chain alkyl group having 1 to 6 carbon atoms; Yhas the same meaning as defined above, in the presence of a basicreagent in an inert solvent, and optionally, hydrolyzing the esterproduct to the corresponding free carboxylic acid.

In the above process, suitable inert solvents include benzene, toluene,tetrahydrofuran, dioxane, acetone, acetonitrile, dimethylsulfoxide,N,N-dimethylformamide, n-butanol, and any other solvent which does notadversely influence this reaction. Suitable basic reagents includepotassium carbonate, sodium carbonate, sodium hydrogen carbonate,triethylamine, and the like.

As an alternative to using a basic reagent, an excess amount of thereactant compound represented by the formula (II) may be employed.

In the above process, the reaction of the compound (II) with thecompound (III) is known as N-alkylation, and can be conducted at atemperature of about 0° to 150° C.

With respect to invention compounds represented by the formula (I), acompound corresponding to the formula: ##STR7## wherein Y¹ represents acovalent bond, or a straight- or branched-chain alkylene group having 1to 6 carbon atoms; X and R have the same meanings as defined above, alsocan be prepared by a reaction of a 2-halogenobenzimidazole compoundrepresented by the formula: ##STR8## wherein z represents a chlorineatom or a bromine atom; X has the same meaning as defined above, with a1,5-diazacyclooctane compound represented by the formula: ##STR9##wherein R¹ and Y¹ have the same meanings as defined above, in thepresence of a basic reagent in the absence or presence of an inertsolvent, and optionally, hydrolyzing the ester product to thecorresponding free carboxylic acid.

In the above process, suitable inert solvents include benzene, toluene,tetrahydrofuran, dioxane, acetone, acetonitrile, dimethylsulfoxide,N,N-dimethylformamide, n-butanol, and any other solvent which does notadversely influence this reaction. Suitable basic reagents includepotassium carbonate, sodium carbonate, sodium hydrogen carbonate,triethylamine, and the like.

As an alternative to using a basic reagent, an excess amount of thereactant compound represented by the formula (V) may be employed.

In the above process, the reaction of the compound (IV) with thecompound (V) is known as N-alkylation, and can be conducted at atemperature of about 0° to 150° C.

The compounds represented by the formula (II) used as the startingmaterials in the process described above are novel, and in one methodcan be prepared by a reaction of the 2-halogenobenzimidazole compoundrepresented by the formula (IV) with 1,5-diazacyclooctane in the absenceor presence of a basic reagent in the absence or presence of an inertsolvent.

The 2-halogenobenzimidazole compounds represented by the formula (IV)used as the starting materials in the process described above includeknown compounds, and can be easily prepared by synthesis methodsreported in the chemical literature or analogous methods thereto.

The compounds represented by the formula (V) used as starting materialsin the process described above are also novel compounds, and in onemethod can be prepared by a reaction of the phenylethyl bromide compoundrepresented by the formula (III) with 1,5-diazabicyclo[3,3,0]octane in anonpolar solvent such as diethyl ether, and then catalytic hydrogenationof the resulting hydrazinium salt compound represented by the formula:##STR10## wherein R¹ and Y have the same meanings as defined above, inan atmosphere of hydrogen employing a hydrogenating catalyst such aspalladium on activated carbon.

The phenylethyl bromide compounds represented by the formula (III) usedas the starting materials can be easily prepared by methods described inliterature, for example, Journal of the American Chemical Society, Vol.107, No.5, pp 1429-1430, 1985, or analogous methods thereto.

If there are one or more asymmetric carbon atoms in the substituent Y,the 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds represented bythe formula (I) of the present invention will consist of asymmetricisomers. The configuration of the compounds of the present invention isnot limited. The R-isomer, S-isomer or a mixture of R-isomer andS-isomer can be employed in the practice of present invention.

If there are one or more unsaturated bonds in the substituent Y, the1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds represented by theformula (I) of the present invention will consist of geometricalisomers. All of the geometrical isomers can be employed in the practiceof the present invention.

Of the 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of thepresent invention, the compounds wherein X is a fluorine atom arepreferred.

Of the 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of thepresent invention, preferred compounds are illustrated by1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2yl]-5-[2-(4-isopropoxycarbonylphenyl)ethyl]-1,5-diazacyclooctane,5-[2-(4-carboxyphenyl)ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane,5-[2-(4-carboxymethylphenyl)ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane,1- [1- ( 4- fluorophenylmethyl )-1H-benzimidazol-2-yl]-5-[2-(4-isopropoxycarbonylmethylphenyl)ethyl]-1,5-diazacyclooctane,1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane,5-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane,5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane,5-[2-[4-(3-ethoxycarbonylpropyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl ]-1,5-diazacyclooctane,5-[2-[4-(4-ethoxycarbonylbutyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl ]-1,5-diazacyclooctane, 5-[2-[4-[(E)-2-ethoxycarbonylvinyl]phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctaneand 5-[2-[4-[(E)-2-carboxyvinyl]phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.

Of the 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of thepresent invention, more preferred compounds are illustrated by1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane,5-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane,5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane,1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-isopropoxycarbonylphenyl)ethyl]-1,5-diazacyclooctane,5-[2-(4-carboxyphenyl)ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane,5-[2-[4-[(E)-2-ethoxycarbonylvinyl]phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctaneand5-[2-[4-[(E)-2-carboxyvinyl]phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.

Of the 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of thepresent invention, the most preferred compound is5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.

The pharmacological activity of the1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of the presentinvention can be confirmed by receptor binding assay in blocking3H-pyrilamine binding to histamine H₁ -receptor site in guinea pigcerebellum. The 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds ofthe present invention show a potent histamine H₁ -receptor antagonisticactivity, and produce a 50% inhibitory activity in a range of about10⁻¹⁰ to 10⁻⁸ M (concentration producing 50% reduction of the binding ofthe labeled ligand). For example,5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctaneproduced a 50% inhibitory activity at about 5.75×10⁻¹⁰ M.

In the guinea pig antigen-induced bronchoconstriction model, the1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of the presentinvention also show a potent antiallergic activity and a long-lastingefficacy. For example, with5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(0.01 mg/ml solution), inhalation for 1 minute (with an ultrasonicnebulizer) inhibited DNP-As (100 μg protein/ml solution, 1 ml/kg, i.v.)-induced bronchoconstriction about 54.6% and about 44.7% at 4 hours and8 hours after inhalation of this compound, respectively. In comparison,inhalation of Astemizole (0.01 mg/ml solution, inhalation for 1 minutewith an ultrasonic nebulizer) inhibited the same DNP-As-inducedbronchoconstriction about 37.5% and about 29.3% at 4 hours and 8 hoursafter the inhalation, respectively.

These findings clearly demonstrated that the compounds of the presentinvention exhibit potent antihistaminic and antiallergic activities anda long-lasting efficacy by topical administration, and are very usefulas therapeutic agents for the treatment of bronchial asthma.

The 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of the presentinvention show a weak cytotoxicity toward normal human epidermalkeratinocytes (NHEK) growth. For example, NR₅₀ (the concentration of thetest compound which causes a 50% reduction in neutral red uptake by atreated cell culture compared with the untreated control culture) valueof5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctaneis about 789 μM. In comparison, the NR₅₀ value of Astemizole is about4.42 μM.

These findings clearly demonstrated that the1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of present inventionhave a very weak cytotoxicity and a weak topical irritation, and thatthey are very useful compounds which can be applied to inhalation to thebronchia.

The 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds represented bythe formula (I) of the present invention can be converted intopharmaceutically acceptable salts thereof according to the conventionalmethods.

The 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of the presentinvention have two basic amino groups, and mono- or di-acids additionsalts thereof can be prepared. Examples of such mono- or di-acidsaddition salts include an inorganic acid addition salt formed withhydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, and an organic acid addition salt formedwith acetic acid, maleic acid, fumaric acid, malic acid, citric acid,oxalic acid, lactic acid, tartaric acid, and the like.

Of the 1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds of thepresent invention, a compound wherein R represents a hydrogen atom canbe converted into sodium salt, potassium salt, calcium salt, and thelike.

When a 1-(2-benzimidazolyl)-1,5-diazacyclooctane compound represented bythe formula (I) of the present invention or a pharmaceuticallyacceptable salt thereof is employed for inhalation, a dry mixture of afine powder of 1-(2-benzimidazolyl)-1,5-diazacyclooctane compound of thepresent invention and an excipient such as lactose, or a solution orsuspension of 1-(2-benzimidazolyl)-1,5-diazacyclooctane compound of thepresent invention in a suitable diluent such as water or ethyl alcohol,can be administered by inhalation using a suitable inhalator ornebulizer. If desired, a fine powder of1-(2-benzimidazolyl)-1,5-diazacyclooctane compound of the presentinvention can be treated with a surface active agent to preventcoaggregation, and a propellant such as air or chlorofluorocarbon can beutilized.

The dosage of 1-(2-benzimidazolyl)-1,5-diazacyclooctane compoundsrepresented by the formula (I) of the present invention may be in therange from about 50 μg to 100 mg per adult human per day depending uponthe age, sex, weight of the patient, the type of disease, severity ofcondition to be treated, and the like.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Reference Examples and Examples.

REFERENCE EXAMPLE 11-[1-(4-Fluorophenylmethyl)-1H-benzimidazol-2-yl-1,5-diazacyclooctane

A mixture of 2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole (10.07 g)and 1,5-diazacyclooctane (5.60 g) was heated at 80° C. for 1 hour. Tothe reaction mixture was added distilled water (300 ml), and the mixturewas extracted with methylene chloride (300 ml). The extract was washedwith water, and dried over anhydrous MgSO₄. The solvent was removedunder reduced pressure to give1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(12.1 g) as a colorless oily liquid.

NMR (CDCl₃) δ: 1.75(t, 4H), 2.96(t, 4H), 3.54(t, 4H), 5.23 (s, 2H),6.97-7.20(m, 7H), 7.58(d, 1H)

REFERENCE EXAMPLE 2

In a similar manner to that described in Reference Example 1, thefollowing compound was prepared by using2-bromo-1-phenylmethyl-1H-benzimidazole instead of2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole.

1-(1-Phenylmethyl-1H-benzimidazol-2-yl)-1,5

NMR (CDCl₃) δ: 1.75(m, 4H), 2.94(m, 4H), 3.55(t, 4H), 5.27 (s, 2H),6.95-7.10 (m, 2H), 7.15-7.20(m, 3H), 7.25-7.35(m, 3H), 7.58(d, 1H)

REFERENCE EXAMPLE 3

In a similar manner to that described in Reference Example 1, thefollowing compound was prepared by using2-bromo-1-(4-chlorophenylmethyl)-1H-benzimidazole instead of2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole.

1-[1-(4-Chlorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.

NMR (CDCl₃) δ: 1.75(m, 4H), 2.92 (t, 4H), 3.56 (t, 4H), 5.25 (s, 2H),6.95(d, 1H),7.05-7.15(m, 3H), 7.20-7.30(m, 3H), 7.59 (d, 1H)

REFERENCE EXAMPLE 4 2-[4-(2-Methoxycarbonylethyl)phenyl]ethyl bromide

A mixture of 4-(2-t-butyldimethylsiloxyethyl)bromobenzene (1.00 g),methyl acrylate (0.55 g), palladium(II) acetate (0.010 g),triphenylphosphine (0.017 g) and N,N,N',N'-tetramethylethylenediamine(0.48 ml) was heated at 140° C. for 24 hours under an atmosphere ofargon. To the reaction mixture was added methylene chloride (30 ml), theformed insoluble materials were removed by filtration through a celitecolumn, and the filtrate was concentrated under reduced pressure. To theresidue was added diethyl ether (30 ml), and the formed insolublematerials were removed by filtration through a celite column. Thefiltrate was concentrated to dryness to give methyl4-(2-t-butyldimethylsiloxyethyl)cinnamate (0.94 g) as a brown oilyliquid.

To a solution of methyl 4-(2-t-butyldimethylsiloxyethyl)cinnamate (1.90g) in ethanol (15 ml) was added a 10% palladium on activated carbon(0.20 g), and the mixture was stirred at room temperature for 4 hoursunder an atmosphere of hydrogen. The catalyst was removed by filtrationthrough a celite column, and the filtrate was concentrated to drynessunder reduced pressure. To the residue was added a 48% hydrobromic acid(15 ml), and the mixture was refluxed for 2 hours. The reaction mixturewas poured into an ice-water, and the resulting precipitates werecollected by filtration. The obtained crystals were dissolved in anaqueous 2N-NaOH solution, and the solution was washed with diethylether. After the aqueous layer was neutralized with a 2N-HCl, theresulting precipitates were collected by filtration, washed with water,and dried at 80° C.

The obtained crystals were dissolved in a methanol (15 ml) solutionsaturated with HCl, and the solution was refluxed for 2 hours. Thesolvent was removed under reduced pressure, the residue was quenchedwith a saturated aqueous NaHCO₃ solution, and the mixture was extractedwith diethyl ether. The extract was dried over anhydrous MgSO₄, andconcentrated to dryness under reduced pressure to give2-[4-(2-methoxycarbonylethyl)phenyl]ethyl bromide (0.80 g) as brownpowder.

NMR (CDCl₃) δ: 2.62 (t, 2H), 2.92 (t, 2H), 3.12 (t, 2H), 3.53 (t, 2H),3.66 (s, 3H), 7.14 (m, 4H)

REFERENCE EXAMPLE 5 2-[4-[(E)-2-Ethoxycarbonylvinyl]phenyl]ethyl bromide

In a similar manner to that described in Reference Example 4, ethyl4-(2-t-butyldimethylsiloxyethyl)cinnamate was prepared by using ethylacrylate instead of methyl acrylate. To a solution of ethyl4-(2.t-butyldimethylsiloxyethyl)cinnamate (1.1 g) in tetrahydrofuran (4ml) was added dropwise tetra-n-butylammonium fluoride (1 mol/l solutionin tetrahydrofuran, 3.5 ml), and the mixture was stirred at roomtemperature for 1.5 hours. The reaction mixture was poured into water,and the mixture was extracted with diethyl ether. The extract was driedover anhydrous MgSO₄, and the solvent was removed under reducedpressure. To a solution of the residue and triphenylphosphine (1.07 g)in methylene chloride (10 ml) was added carbon tetrabromide (1.35 g),and the mixture was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure. To the residuewas added n-hexane, and the insoluble materials were removed byfiltration. The filtrate was concentrated under reduced pressure, andthe residue was purified by medium pressure liquid column chromatographyon a silica gel column using a mixture of methylene chloride andn-hexane (1:1) as eluent to give2-[4-[(E)-2-ethoxycarbonylvinyl]phenyl]ethyl bromide (0.77 g) as ancolorless oily liquid.

NMR (CDCl₃) δ: 1.32(t, 3H), 3.18(t, 2H), 3.56(t, 2H), 4.28 (q, 2H),6.42(d, 1H, J=16.0 Hz), 7.24(d, 2H), 7.48 (d, 2H), 7.66(d, 1H, J=16.0Hz)

REFERENCE EXAMPLE 6

2-[4-(3-Ethoxycarbonylpropyl)phenyl]ethyl bromide

To a solution of ethyl 4-(2-t-butyldimethylsiloxyethyl)cinnamate (1.9 g)in tetrahydrofuran (6 ml) was added dropwise tetra-n-butylammoniumfluoride (1 mol/l solution in tetrahydrofuran, 6.0 ml), and the mixturewas stirred at room temperature for 1.5 hours. To the reaction mixturewas added water, and the mixture was extracted with diethyl ether. Theextract was dried over anhydrous MgSO₄. The solvent was removed underreduced pressure, and the residue was treated according to C. J.Kowalski's method described in J. Am. Chem. Soc., Vol.107, No.5,1429-1430 (1985) to give 2-[4-(3-ethoxycarbonyl-1-propenyl)phenyl]ethylalcohol (0.42 g) as colorless powder.

To a solution of 2-[4-(3-ethoxycarbonyl-1-propenyl)phenyl]ethyl alcohol(0.42 g) in ethanol was added a 10% palladium on activated carbon (0.05g), and the mixture was stirred at room temperature for 2 hours under anatmosphere of hydrogen. The catalyst was removed by filtration through acelite column, and the filtrate was concentrated under reduced pressure.To a solution of the residue and triphenylphosphine (0.55 g) inmethylene chloride (5 ml) was added carbon tetrabromide (0.70 g), andthe mixture was stirred at room temperature for 30 minutes. The solventwas removed under reduced pressure, and the residue was purified bymedium pressure liquid column chromatography on a silica gel columnusing a mixture of n-hexane and methylene chloride (3:1) as eluent togive 2-[4-(3-ethoxycarbonylpropyl)phenyl]ethyl bromide (0.31 g) as acolorless oily liquid.

NMR (CDCl₃) δ: 1.22(t, 3H), 1.94(m, 2H), 2,30(t, 2H), 2.62 (m, 2H),3.12(t, 2H),3.53(t, 2H), 4.11(q, 2H), 7.12 (brs, 4H)

REFERENCE EXAMPLE 7 2-[4-(4-Ethoxycarbonylbutyl)phenyl]ethyl bromide

To a solution of 4-(2-t-butyldimethylsiloxyethyl)bromobenzene (4.29 g)in tetrahydrofuran (30 ml) was added n-butyllithium (1.64 mol/l solutionin tetrahydrofuran, 9.0 ml) at -78° C., and the mixture was stirred atthe same temperature for 15 minutes. To the reaction mixture was addedN,N-dimethylformamide (1.3 ml), and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was poured into water,and the mixture was extracted with diethyl ether. The extract wasconcentrated to dryness under reduced pressure to give4-(2-t-butyldimethylsiloxyethyl)benzaldehyde(3.59 g)To a solution ofethyl triphenylphosphranylidenebutylate (2.22 g), which was preparedfrom (3-carboethoxypropyl)triphenylphosphonium bromide and sodiumbis(trimethylsilyl)amide, in tetrahydrofuran (25 ml) was added4-(2-t-butyldimethylsiloxyethyl)benzaldehyde (1.57 g) at -78° C., andthe mixture was stirred at the same temperature for 4 hours and allowedto stand at room temperature for 12 hours. The reaction mixture waspoured into water, and the mixture was extracted with diethyl ether. Theextract was washed with brine, dried over anhydrous MgSO₄, and thesolvent was removed under reduced pressure. To a solution of the residuein acetonitrile (80 ml) was added a 47% hydrofluoric acid (1 ml), andthe mixture was stirred at room temperature for 1 hour. The solvent wasconcentrated under reduced pressure. The residue was dissolved inchloroform, the solution was washed with a saturated aqueous NaHCO₃solution, and dried over anhydrous MgSO₄. The solvent was removed underreduced pressure. The residue was purified by medium pressure liquidcolumn chromatography on a silica gel column using a mixture ofmethylene chloride, diethyl ether and methanol (1:1:1) as eluent to give2-[4-(4-ethoxycarbonyl-1-butenyl)phenyl]ethyl alcohol (0.35 g).

To a solution of 2-[4-(4-ethoxycarbonyl-1-butenyl)phenyl]ethyl alcohol(0.33 g) in ethanol (10 ml) was added a 10% palladium on activatedcarbon (0.030 g), and the mixture was stirred at room temperature for 3hours under an atmosphere of hydrogen. The catalyst was removed byfiltration through a celite column, and the solvent was removed underreduced pressure. To a solution of the residue in methylene chloride (5ml) were added triphenylphosphine (0.387 g) and carbon tetrabromide(0.489 g), and the mixture was stirred at room temperature for 30minutes. The reaction mixture was concentrated under reduced pressure.To the residue was added a mixture of diethyl ether and n-hexane (1:1),and the insoluble materials were removed by filtration. The filtrate wasconcentrated to dryness under reduced pressure to give2-[4-(4-ethoxycarbonylbutyl)phenyl]ethyl bromide (0.52 g) as an oilyliquid.

NMR (CDCl₃) δ: 1.25(t, 3H), 1.60-1.70(m, 4H), 2.21(m, 2H), 2.60 (m, 2H),3.14 (t, 2H), 3.55 (t, 2H), 4.12 (q, 2H), 7.10-7.15 (brs, 4H)

REFERENCE EXAMPLE 8 2-[4-(2-Methoxycarbonyl-2-methylpropyl)phenyl]ethylbromide

To a solution of methyl 4-(2-t-butyldimethylsiloxyethyl)cinnamate (1.53g) in ethanol (25 ml) was added a 10% palladium on activated carbon(0.15 g), and the mixture was stirred at room temperature for 2 hoursunder an atmosphere of hydrogen. The catalyst was removed by filtration,and the filtrate was concentrated under reduced pressure. To a solutionof the residue in tetrahydrofuran (35 ml) was added lithiumbis(trimethylsilyl)amide (1.0 mol/l solution in tetrahydrofuran, 3.9 ml)at -78° C., and the mixture was stirred at the same temperature for 30minutes. To the reaction mixture was added a solution of iodomethane(0.533 g) in tetrahydrofuran (2 ml), and the mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added water, and themixture was extracted with diethyl ether. The extract was washed withwater, and dried over anhydrous MgSO₄. The solvent was removed underreduced pressure, and the residue was purified by medium pressure liquidcolumn chromatography on a silica gel column using a mixture of n-hexaneand methylene chloride (3:1) as eluent to give1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene(0.724 g) as a colorless oily liquid.

To a solution of lithium diisopropylamide (0.1 mol/l solution intetrahydrofuran, 15 ml) was added a solution of1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene(0.62 g) in tetrahydrofuran (2 ml) at -78° C., and the mixture wasstirred at the same temperature for 30 minutes. To the reaction mixturewas added a solution of iodomethane (0.20 g) in tetrahydrofuran (2 ml),and the mixture was stirred at room temperature for 4 hours. To thereaction mixture was added water, and the mixture was extracted withdiethyl ether. The extract was washed with water, and dried overanhydrous MgSO₄. The solvent was removed under reduced pressure, and theresidue was purified by medium pressure liquid column chromatography ona silica gel column using a mixture of n-hexane and methylene chloride(3:1) as eluent to give1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene(0.49 g) as an oily liquid. To a solution of1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene(0.49 g) in tetrahydrofuran (1.5 ml) was added tetra-n-butylammoniumfluoride (1 mol/l solution in tetrahydrofuran, 1.34 ml), and the mixturewas stirred at room temperature for 1 hour. To the reaction mixture wasadded water, and the mixture was extracted with diethyl ether. Theextract was washed with water, and dried over anhydrous MgSO₄. Thesolvent was removed under reduced pressure, and the residue was purifiedby medium pressure liquid column chromatography on a silica gel columnusing a mixture of methylene chloride and diethyl ether (7:1) as eluentto give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol(0.300 g) as an oily liquid. To a solution of2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) inmethylene chloride (3 ml) were added carbon tetrabromide (0.48 g) andtriphenylphosphine (0.38 g), and the mixture was stirred at roomtemperature for 1 hour. The solvent was removed under reduced pressure,and the residue was purified by medium pressure liquid columnchromatography on a silica gel column using a mixture of n-hexane andmethylene chloride (3:1) as eluent to give2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide (0.323 g) asan oily liquid.

NMR (CDCl₃) δ: 1.18(s, 6H), 2.83(s, 2H), 3.15(t, 2H), 3.55 (t, 2H),3.67(s, 3H),7.09(m, 4H)

REFERENCE EXAMPLE 9

In a similar manner to that described in Reference Example 8, thefollowing compound was prepared by using ethyl4-(2-t-butyldimethylsiloxyethyl)cinnamate instead of methyl4-(2-t-butyldimethylsiloxyethyl)cinnamate.

2-[4-(2-Ethoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide.

NMR (CDCl₃) 1.19(s, 6H), 1.22(t, 3H), 2.83(s, 2H), 3.15 (t, 2H), 3.52(t,2H),4.10(q, 2H), 7.09(m, 4H)

REFERENCE EXAMPLE 101-[2-[4-(2-Ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane

To a solution of 2-[4-[(E)-2-ethoxycarbonylvinyl]phenyl]ethyl bromide(2.10 g) in diethyl ether (20 ml) was added1,5-diazabicyclo[3,3,0]octane (0.89 g), and the mixture was stirred atroom temperature for 16 hours. The solvent was removed under reducedpressure. To a solution of the residue in ethanol (30 ml) was added a10% palladium on activated carbon (0.44 g), and the mixture was stirredat room temperature for 5 hours under an atmosphere of hydrogen. Thecatalyst was removed by filtration through a celite column, and thefiltrate was concentrated under reduced pressure. The residue wasquenched with an aqueous 1N-NaOH solution (20 ml), and the mixture wasextracted with methylene chloride (30 ml). The extract was dried overanhydrous MgSO₄, and concentrated to dryness under reduced pressure togive 1-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane(2.46 g) as a colorless oily liquid.

NMR (CDCl₃) δ: 1.24(t, 3H), 1.63(brs, 4H), 2.57-2.78(m, 10H), 2.85 (brs,4H), 2.93 (t, 2H), 4.12 (q, 2H), 7.12 (brs, 4H)

REFERENCE EXAMPLE 11

In a similar manner to that described in Reference Example 10, thefollowing compound was prepared by using2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide instead of2-[4-[(E)-2-ethoxycarbonylvinyl]phenyl]ethyl bromide.

1-[2-[4-(2-Methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane.

NMR (CDCl₃) δ: 1.17 (s, 6H), 1.65 (m, 4H), 2.60-2.80 (m, 8H), 2.84(s,2H), 2.90 (m, 4H), 3.66(s, 3H), 7.02 (d, 2H), 7.10(d, 2H)

EXAMPLE 11-[1-(4-Fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane(compound 1)

To a solution of1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(12.1 g) in N,N-dimethylformamide (70 ml) were added4-(2-methoxycarbonylethyl)phenethyl bromide (9.49 g), sodium carbonate(3.71 g) and potassium iodide (0.58 g), and the mixture was heated at100° C. for 1 hour. The reaction mixture was poured into an ice-water(200 ml), and the mixture was extracted with methylene chloride (200ml). The extract was washed with water, and dried over anhydrous MgSO₄.The solvent was removed under reduced pressure, and the residue waspurified by medium pressure liquid column chromatography on a silica gelcolumn using a mixture of methylene chloride, diethyl ether and methanol(1:1:0.25) as eluent to give1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane(11.38 g) as a colorless oily liquid.

NMR (CDCl₃) δ: 1.77(t, 4H), 2.58(t, 2H), 2.71(t, 2H), 2.88 (m, 8H), 3.48(m, 4H), 3.65 (s, 3H), 5.17 (s, 2H), 6.95-7.20 (m, 11H), 7.52 (d, 1H) IR(neat): 1740, 1540, 1510 cm⁻¹

EXAMPLE 2

In a similar manner to that described in Example 1, the followingcompounds were prepared by using corresponding phenethyl bromidederivative instead of 4-(2-methoxycarbonylethyl)phenethyl bromide.

1-[1-(4-Fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane(compound 2)

NMR (CDCl₃) δ: 1.15(s, 6H), 1.80 (brs, 4H), 2.65-2.95 (m, 10H), 3.50(m,4H), 3.65(s, 3H), 5.18(s, 2H), 6.92-7.23(m, 11H), 7.55 (d, 1H) IR(neat): 1740, 1540, 1510 cm⁻¹ Mass (FAB) M/Z: 557 (M+H)⁺

5-[2-[4-(E)-2-Ethoxycarbonylvinyl]phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(compound 3)

NMR (CDCl₃) δ: 1.34 (t, 3H), 1.77 (m, 4H), 2.7 6 (m, 8H), 3.50 (m, 4H),4.26(q, 2H),5.12(s, 2H), 6.36(d, 1H, J=16.0 Hz), 6.90-7.20 (m, 9H), 7.38(d, 2H), 7.55 (d, 1H), 7.63 (d, 1H, J=16.0 Hz)

5-[2-[4-(2-Ethoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(compound 4)

NMR (CDCl₃) δ: 1.14(s, 6H), 1.24(t, 3H), 1.78(bs, 4H), 2.65-2.85(m,10H), 3.50(m, 4H), 4.10(q, 2H), 5.18 (d, 2H), 6.92-7.20 (m, 11H), 7.55(d, 1H)

5-[2-[4-(3-Ethoxycarbonylpropyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(compound 5)

NMR (CDCl₃) δ: 1.25 (t, 3H), 1.80 (brs, 4H), 1.92 (m, 2H), 2.30 (t, 2H),2.60(t, 2H), 2.78(brs, 8H), 3.52(m, 4H), 4.12(q, 2H), 5.18(s, 2H),6.93-7.20 (m, 11H), 7.55 (d, 1H)

5-[2-[4-(4-Ethoxycarbonylbutyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(compound 6)

NMR (CDCl₃) δ: 1.25(t, 3H), 1.65(m, 4H), 1.78(brs, 2H), 1.85 (brs, 2H),2.31 (t, 2H), 2.60 (m, 2H), 2.70-2.90 (m, 8H), 3.51(m, 4H), 5.18(s, 2H),6.95-7.20 (m, 11H), 7.55 (d, 1H)

1-[1-(1-Fluorophenylmethyl)-1H-benzimidazol-2-yl]- 5-[2-(4-isopropoxycarbonylphenyl)ethyl]-1,5-diazacyclooctane (compound 7)

NMR (CDCl₃) δ: 1.38(d, 6H), 1.79(m, 4H), 2.78(m, 4H), 2.83 (bs, 4H),3.53(m, 4H), 5.18(s, 2H), 5.26 (m, 1H), 6.98-7.28 (m, 9H), 7.57 (d, 1H),7.96 (d, 2H)

1-[1-(4-Fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-(4-isopropoxycarbonylmethylphenyl)ethyl]-1,5-diazacyclooctane(compound 8)

NMR (CDCl₃) δ: 1.23 (d, 6H), 1.78(brs, 4H), 2.78(brs, 8H), 3.51(t, 6H),4.95 (m, 1H), 5.18 (s, 2H), 6.95-7.19 (m, 11H), 7.55 (d, 1H) IR (neat):1726, 1510 cm⁻¹ Mass (FAB) M/Z: 543 (M+H)⁺

EXAMPLE 3

In a similar manner to that described in Example 1, the followingcompound was prepared by using1-[1-(4-chlorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctaneinstead of1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane,and using 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromideinstead of 4-(2-methoxycarbonylethyl)phenethyl bromide.

1-[1-(4-Chlorophenylmethyl)-1H-benzimidazol-2-yl]-5-]2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane(Compound 9).

NMR (CDCl₃) δ: 1.15(s, 6H), 1.75(m, 4H), 2.60-2.90(m, 10H), 3.50(m, 4H),3.65 (s, 3H), 5.18(s, 2H), 6.90-7.40 (m, 11H), 7.55 (d, 1H) IR (neat):1740, 1540 cm⁻¹ Mass (FAB) M/Z: 573 (M+H)⁺

EXAMPLE 45-[2-[4-(2-Carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (Compound 10)

To a solution of1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane(6.479) in methanol (100 ml) was added an aqueous 2N-NaOH solution (9.2ml), and the mixture was heated at 60° C. for 1 hour. The solvent wasremoved under reduced pressure, and the residue was purified by mediumpressure liquid column chromatography on an ODS column using a mixtureof methanol and water (65:35) as eluent to give5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (5.74 g) as white powder.

NMR (CDCl₃) δ: 1.62(brs, 4H), 2.42(brs, 2H), 2.58 (brs, 8H), 2.74(brs,2H), 3.32(brs, 4H), 5.05(brs,2H), 6.70-7.10 (m, 11H), 7.42 (d, 1H) IR(KBr): 1600, 1560, 1540 cm¹ Mass (FAB) M/Z: 537 (M+H)⁺

EXAMPLE 5

In a similar manner to that described in Example 4, the followingcompounds were prepared by treating the corresponding compound inExample 2 instead of1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4 -(2-methoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane.

5-[2-(4-Carboxyphenyl)ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (compound 11)

NMR (DMSO-d₆) δ: 1.83(m, 4H), 2.78(m, 4H), 2.82(m, 4H), 3.58 (m, 4H),5.43(s, 2H),7.07(m, 1H), 7.14-7.31 (m, 8H), 7.43 (d, 1H), 7.84(d, 2H) IR(KBr): 1550, 1590 cm⁻¹ Mass (FAB) M/Z: 509 (M+H)⁺

5-[2-(4-Carboxymethylphenyl)ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt compound 12)

NMR (CDCl₃) δ: 1.64(brs, 4H), 2.59 (brs, 8H), 3.24 (brs, 2H), 3.39 (brs,4H), 5.08(s, 2H), 6.86-7.15(m, 11H), 7.50 (d, 1H) IR (neat): 1545, 1510cm⁻¹ Mass (FAB) M/Z: 523 (M+H) ⁺

5-[2-[4-(3-Carboxypropyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (compound 13)

NMR (CDCl₃) δ: 1.55-1.85(m, 6H), 2.08 (brs, 2H), 2.39 (brs, 2H),2.50-2.75 (m, 8H), 3.43(brs, 4H), 5.10(s, 2H), 6.80-7.20(m, 11H), 7.51(d, 1H) IR (neat): 1600, 1550, 1515 cm⁻¹ Mass (FAB) M/Z: 551 (M+H) ⁺

5-[2-[4-(4-Carboxybutyl]phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (compound 14)

NMR (CDCl₃) δ: 1.58(brs, 4H), 1.75(brs, 4H), 2.18(brs, 2H), 2.50-2.70(m,10H), 3.50(brs, 4H), 5.15(brs, 2H), 6.90-7.20 (m, 11H), 7.52 (d, 1H) IR(neat): 1560, 1550, 1510 cm⁻¹ Mass (FAB) M/Z: 565 (M+H)⁺

5-2-4-[(E)-2-Carboxyvinyl]phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (compound 15)

NMR (CDCl₃) δ: 1.65(brs, 4H), 2.42-2.70(m, 8H), 3.40(brs, 4H), 5.03(brs,2H),6.31(m, 1H), 6.60-7.20 (m, 11H), 7.33(m, 1H), 7.46(brs, 1H) IR(KBr): 1640, 1605, 1545, 1515 cm⁻¹ Mass (FAB) M/Z: 535 (M+H)⁺

EXAMPLE 65-[2-[4-(2-Carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(compound 16)

A pH of a solution of 5- [2- [4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (5.15 g) in distilled water (100 ml) was adjusted to pH 7with a 2N-HCl. The resulting white precipitates were collected byfiltration, washed with distilled water, and air-dried to give 5- [2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(4.30 g) as white crystals.

NMR (CDCl₃) δ: 1.65(m, 4H), 2.66(m, 8H), 2.82(t, 2H), 2.95 (t, 2H), 3.11(m, 4H), 5.12 (s, 2H), 6.95-7.20 (m, 11H), 7.52(d, 1H) IR (KBr): 1610,1540, 1515 cm⁻¹ Melting Point: 76°-78° C. Mass (FAB) M/Z: 515 (M+H)⁺

EXAMPLE 7

In a similar manner to that described in Example 6, the followingcompound was prepared by treating5-[2-[4-(2-carboxy-2-methylpropyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt which was prepared from1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctaneor5-[2-[4-(2-ethoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanein Example 2 in a similar manner to that described in Example 4, insteadof5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt.

5-[2-[4-(2-Carboxy-2-methylpropyl)phenyl]ethyl]-yl-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(Compound 17)

NMR (CDCl₃) δ: 1.04 (brs, 6H), 1.66 (brs, 4H), 2.55-2.80 (m, 10H),3.34(brs, 4H), 5.10(s, 2H), 6.90-7.15 (m, 11H), 7.53 (d, 1H) IR (neat):1610, 1540, 1510 cm⁻¹ Mass (FAB) M/Z: 543 (M+H) ⁺

EXAMPLE 81-[1-(4-Fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-2-isopropoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane(compound 18)

A solution of5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (163 mg) in an isopropanol solution saturated with HCl wasrefluxed for 4 hours. The solvent was removed under reduced pressure,and the residue was dissolved in methylene chloride (20 ml). Thesolution was washed with a saturated aqueous NaHCO₃ solution and brine.The organic layer was dried over anhydrous MgSO₄. The solvent wasremoved under reduced pressure, and the residue was purified by mediumpressure liquid column chromatography on a silica gel column using amixture of methylene chloride, diethyl ether and methanol (1:1:0.25) aseluent to give1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-isopropoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane(123mg) as a colorless oily liquid.

NMR (CDCl₃) δ: 1.20(d, 6H), 1.77 (m, 4H), 2.55(t, 2H), 2.73 (m, 8H),2.89(t, 2H), 3.53 (m, 4H), 4.95 (m, 1H), 5.18 (s, 2H), 6.95-7.20 (m,11H), 7.56 (d, 1H) IR (neat): 1730, 1540, 1510, 1480 cm⁻¹

EXAMPLE 9

In a similar manner to that described in Example 8, the followingcompounds were prepared by treating the corresponding sodium saltcompound in Example 4 and 5 instead of5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt.

1-[1-(4-Fluorophenylethyl)-1H-benzimidazol-2-yl-5-[2-[4-(3-isopropoxycarbonylpropyl)phenyl]ethyl]-1,5-diazacyclooctane(compound 19)

NMR (CDCl₃) δ: 1.23(d, 6H), 1.79 (brs, 4H), 1.91 (m, 2H), 2.28(t, 2H),2.60 (t, 2H), 2.78 (brs, 8H), 3.52 (m, 4H), 5.00 (m, 1H), 5.17 (s, 2H),6.90-7.20(m, 11H), 7.55 (d, 1H) IR (neat): 1730, 1540, 1520 cm⁻¹

1-[1-(4-Fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(4-isopropoxycarbonylbutyl)phenyl]ethyl]-1,5-diazacyclooctane(compound 20)

NMR (CDCl₃) δ: 1.21(d, 6H), 1.62(m, 4H), 1.78 (brs, 4H), 2.28 (t, 2H),2.58(t, 2H), 2.70-2.80 (m, 8H), 3.55 (m, 4H), 4.99(m, 1H), 5.18(s, 2H),6.95-7.20 (m, 11H), 7.55(d, 1H) IR (neat): 1730, 1540, 1515 cm⁻¹

1-[1-(4-Fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-[(E)-2-isopropoxycarbonylvinyl)phenyl]ethyl]-1,5-diazacyclooctane(compound 21)

NMR (CDCl₃) δ: 1.31(d, 6H), 1.77(m, 4H), 2.75(m, 8H), 3.50 (m, 4H),5.07-5.21 (m, 3H), 6.34 (d, 1H, J=16.0 Hz), 6.90-7.20(m, 9H), 7.39(d,2H), 7.55 (d, 1H), 7.60 (d, 1H, J=16.0 Hz) IR (neat): 1710, 1640, 1610,1545, 1515 cm⁻¹ Mass (FAB) M/Z: 555 (M+H) ⁺

5-[2-[4-(2-n-Butoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(compound 22)

NMR (CDCl₃) δ: 0.92(t, 3H), 1.35(m, 2H), 1.58(m, 2H), 1.78 (brs, 4H),2.60(t, 2H), 2.75(m, 8H), 2.90 (t, 2H), 3.51(m, 4H), 4.07(t, 2H), 5.17(s, 2), 6.93-7.20(m, 11H), 7.56(d, 1H)

EXAMPLE 105-[2-[4-(2-Carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (compound 23)

To a solution of 2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole(0.244 g) in n-butanol (1 ml) was added1-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane (1.00g), and the mixture was refluxed for 2 hours. To the reaction mixturewas added a saturated aqueous NaHCO₃ solution (50 ml), and the mixturewas extracted with methylene chloride (30 ml). The extract was washedwith water, and dried over anhydrous MgSO₄. The solvent was removedunder reduced pressure, and the residue was purified by medium pressureliquid column chromatography on a silica gel column using a mixture ofmethylene chloride, diethyl ether and methanol (1:1:0.25) as eluent togive a mixture (0.369 g) of5-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctaneand5-[2-[4-(2-n-butoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.

To a solution of the mixture (0.369 g) of5-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctaneand5-[2-[4-(2-n-butoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanein methanol (3 ml) was added an aqueous 1N-NaOH solution (0.62 ml), andthe mixture was stirred at 60° C. for 1 hour. The solvent was removedunder reduced pressure, and the residue was purified by medium pressureliquid column chromatography on an ODS column using a mixture ofmethanol and water (65:35) as eluent to give5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt (0.117 g) as white powder.

Physical and spectral characteristics of the obtained compound abovewere identical with that of compound 10.

EXAMPLE 111-[1-]4-Chlorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane(compound 24)

To a solution of 2-bromo-1-(4-chlorophenylmethyl)-1H-benzimidazole(0.029 g) in n-butanol (0.5 ml) was added1-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane(0.102 g), and the mixture was refluxed for 3 hours. The reactionmixture was quenched with a saturated aqueous NaHCO₃ solution (30 ml),and the mixture was extracted with methylene chloride (20 ml). Theextract was washed with water, and dried over anhydrous MgSO₄. Thesolvent was removed under reduced pressure, and the residue was purifiedby medium pressure liquid column chromatography on a silica gel columnusing a mixture of methylene chloride, diethyl ether and methanol(1:1:0.2) as eluent to give1-[1-(4-chlorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane(0.030 g) as a colorless oily liquid.

Physical and spectral characteristics of the obtained compound abovewere identical with that of compound 9.

EXAMPLE 12

In a similar manner to that described in Example 11, the followingcompound was prepared by using 1- [2- [4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane instead of1-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane.

1-[1-(4-Chlorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane(compound 25)

NMR (CDCl₃) δ: 1.23(t, 3H), 1.77(m, 4H), 2.58(t, 2H), 2.74 (m, 8H), 2.89(t, 2H), 3.50 (m, 4H), 4.12 (q, 2H), 5.16 (s, 2H), 6.94 (d, 1H),7.00-7.12 (m, 7H), 7.17(t, 1H), 7.30(d, 2H), 7.55(d, 1H)

EXAMPLE 13

In a similar manner to that described in Example 11, the followingcompound was prepared by using2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole instead of2-bromo-1-(4-chlorophenylmethyl)-1H-benzimidazole, and using1-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctaneinstead of1-[2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl]-1,5-diazacyclooctane.

5-[2-[4-(2-Ethoxycarbonylethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(Compound 26)

NMR (CDCl₃) δ: 1.24(t, 3H), 1.78(brs, 4H), 2.69(t, 2H), 2.74 (m, 8H),2.90(t, 2H), 3.52(m, 4H), 4.12 (q, 2H), 5.17 (s, 2H), 6.93-7.20 (m,11H), 7.56 (d, 1H)

EXAMPLE 14

In a similar manner to that described in Example 6, the followingcompound was prepared by treating5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-chlorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctanesodium salt which was prepared from1-[1-(4-chlorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctanein Example 12 in a similar manner to that described in Example 4,instead of 5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane sodiumsalt.

5-[2-[4-(2-Carboxyethyl)phenyl]ethyl]-1-[1-(4-chlorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(Compound 27)

NMR (CDCl₃) δ: 1.62 (brs, 4H), 2.30-2.90 (m, 12H), 3.35 (brs, 4H),5.07(brs, 2H), 6.80-7.14(m, 9H), 7.20 (d, 2H), 7.50 (d, 1H) IR (neat):1560, 1540 cm⁻¹ Mass (FAB) M/Z: 531 (M+H) ⁺

EXAMPLE 155-[2-[4-(2-Carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2yl]-1,5-diazacyclooctane.1H₂SO₄ (Compound 28)

To a solution of5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane(5.50 g) in methanol (35 ml) was added at once a 10% sulfuric acid (10ml) under ice-cooling. The resulting precipitates were collected byfiltration, dried at 60° C. under reduced pressure to give5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.1H₂SO₄ (6.18 g) as white crystals.

NMR (DMSO-d₆) δ: 2.02(brs, 4H), 2.50(t, 2H), 2.80(t, 2H), 2.95 (m, 2H),3.34(m, 2H), 3.42(m, 4H), 3.52 (m, 4H), 5.35(s, 2H), 7.05-7.30(m, 11H),7.45 (d, 1H) IR (KBr): 1690, 1630, 1510 cm⁻¹ Elemental Analysis (for C₃₁H₃₅ N₄ O₂ F.H₂ SO₄)

    ______________________________________                                                C %         H %    N %                                                ______________________________________                                        Calcd.    60.77         6.09   9.14                                           Found     60.89         6.09   9.15                                           ______________________________________                                    

EXAMPLE 165-[2-[4-(2-Carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.0.5H₂SO₄ monohydrate (Compound 29)

To a solution of 5- [2- [4- (2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane (0.5 g)in methanol (15 ml) and water (5 ml) was added slowly a 10% sulfuricacid (4.9 ml). The resulting precipitates were collected by filtration,and dried under reduced pressure at 50° C. to give5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane.0.5H₂SO₄ monohydrate (4.36 g) as white crystals.

NMR (DMSO-d₆) δ: 1.92 (brs, 4H), 2.51 (t, 2H), 2.71 (t, 2H), 2.85 (m,2H), 3.05-3.30 (m, 6H), 3.50 (m, 4H), 5.32 (s, 2H), 7.05(t, 1H),7.10-7.30(m, 11H), 7.45 (d, 1H) IR (KBr): 1690, 1620, 1515 cm⁻¹Elemental Analysis (for C₃₁ H₃₅ N₄ O₂ F.0.5H₂ SO₄.H₂ O)

    ______________________________________                                                C %         H %    N %                                                ______________________________________                                        Calcd.    64.01         6.58   9.63                                           Found     64.26         6.29   9.51                                           ______________________________________                                    

We claim:
 1. A 1-(2-benzimidazolyl)-1,5-diazacyclooctane compoundrepresented by the formula: ##STR11## wherein X represents a hydrogenatom or a halogen atom; Y represents a covalent bond, a straight- orbranched-chain alkylene group having 1 to 6 carbon atoms, or a straight-or branched-chain alkenylene group having 2 to 6 carbon atoms; Rrepresents a hydrogen atom, or a straight- or branched-chain alkyl grouphaving 1 to 6 carbon atoms; or pharmaceutically acceptable saltsthereof.
 2. A 1-(2-benzimidazolyl)-1,5-diazacyclooctane compound asclaimed in claim 1, represented by the formula: ##STR12## wherein Yrepresents a covalent bond, a straight- or branched-chain alkylene grouphaving 1 to 6 carbon atoms, or a straight- or branched-chain alkenylenegroup having 2 to 6 carbon atoms; R represents a hydrogen atom, or astraight- or branched-chain alkyl group having 1 to 6 carbon atoms; orpharmaceutically acceptable salts thereof.
 3. The compound, as claimedin claim 2, represented by the formula: ##STR13## ; or pharmaceuticallyacceptable salts thereof.
 4. The compound, as claimed in claim 2,represented by the formula: ##STR14## ; or pharmaceutically acceptablesalts thereof.
 5. The compound, as claimed in claim 2, represented bythe formula: ##STR15## ; or pharmaceutically acceptable salts thereof.6. A pharmaceutical composition for the treatment of bronchial asthmacontaining, as an active ingredient, a1-(2-benzimidazolyl)-1,5-diazacyclooctane compound represented by theformula: ##STR16## wherein X represents a hydrogen atom or a halogenatom; Y represents a covalent bond, a straight- or branched-chainalkylene group having 1 to 6 carbon atoms, or a straight- orbranched-chain alkenylene group having 2 to 6 carbon atoms; R representsa hydrogen atom, or a straight- or branched-chain alkyl group having 1to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.
 7. Apharmaceutical composition as claimed in claim 6, wherein said activeingredient is the compound represented by the formula: ##STR17## ; or apharmaceutically acceptable salt thereof.
 8. A method for the treatmentof bronchial asthma, which comprises inhaling to the bronchia atherapeutically effective amount of a1-(2-benzimidazolyl)-1,5-diazacyclooctane compound or a pharmaceuticallyacceptable salt thereof of claim
 1. 9. The method, as claimed in claim1, wherein said compound is the compound represented by the formula:##STR18## ; or a pharmaceutically acceptable salt thereof.